The objective of the proposed research is the synthesis of 2-amino-4-hydroxypterin compounds that are designed to inhibit the enzymatic conversion of dihydroneopterin into 6-hydroxymethyldihydropterin catalyzed by neopterin aldolase. Inhibitors will be of both the reversible and "kcat" or "suicide inhibitor" type. Compounds demonstrated to be active against neopterin aldolase should prove active against microorganisms and fungi that utilize the de novo guanosine triphosphate-to-folic acid biosynthetic pathway. These compounds will possess low mammalian toxicity. Also, these enzyme inhibitors could exhibit a unique triple synergistic activity when combined with para-aminobenzoic acid competitors (e.g., sulfonamides, sulfones) and folate reductase inhibitors (e.g., trimethoprim). Dual synergy with sulfa drugs would attack only the microbial de novo folate system and would completely bypass interaction with the mammalian folate system.